This Costimulation PPG grant is driven by the fundamental and therapeutic importance of T cell costimulation for regulating T cell activation and tolerance. The growing number of T cell costimulatory pathways together with the dynamic nature of the immune response suggests that there may be a functional hierarchy of costimulatory molecules for regulating responses of na[unreadable]ve, effector, and memory T cells. Understanding the functions of T cell costimulatory pathways in specific disease models should enable manipulation of costimulatory signals to promote T cell activation or T cell tolerance for therapeutic purposes. The major objectives of the Costimulation PPG is to develop an understanding of the roles of T cell costimulatory pathways in regulating T cell activation and tolerance in defined experimental models of transplantation, autoimmunity, allergy/asthma, and infections. We will address the following questions: 1. Are T cell costimulatory pathways merely redundant or do they provide distinct and unique functions in different types of immune responses? 2. What are the important and unique interactions between the various pathways? 3. What are the effects and mechanisms of targeting of these pathways in vivo? Other objectives include fostering interactions between experts in the field, developing novel tools (animals and reagents) to share among investigators, and building a network of collaborations to share ideas, models and reagents. We plan to achieve these objectives by: 1. identifying, targeting and studying the functions of new costimulatory pathways in well defined experimental models in vivo; 2) analyzing the interactions among the new, and with the well characterized T cell costimulatory pathways in these models. We are proposing 4 Projects (Transplantation, Autoimmunity, Allergy/Asthma, Infections) and 4 Cores (Administrative, Molecular/Signaling, Transgenic/Knockout, Biophysical Characterization). The Administrative Core will be responsible for providing scientific direction and coordination, fiscal oversight and administrative support for the PPG among 7 institutions in 5 different cities. This PPG should provide fundamental knowledge for developing novel translational research opportunities aimed at inducing T cell tolerance to prevent transplant rejection and ameliorate autoimmune and allergic diseases, as well as developing more effective immunity to microbes.